Derivatives of pyrrolizine, indolizine and quinolizine, preparation thereof and therapeutic use thereof

ABSTRACT

The disclosure relates to a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein m, n, Ar, and R are as defined in the disclosure, to compositions containing them and to their therapeutic use. The disclosure also relates to processes for preparing these compounds and to certain intermediate compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/407,276, now allowed, which is a continuation of Internationalapplication No. PCT/FR2007/001545, filed Sep. 21, 2007, which isincorporated herein by reference in its entirety; which claims thebenefit of priority of French Patent Application No. 0608348, filed Sep.22, 2006.

A subject-matter of the present invention is pyrrolizine, indolizine andquinolizine derivatives, their preparation and their therapeuticapplication.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula (I)

in which:m and n each represent, independently of one another, the number 1 or 2,Ar represents a group chosen from the phenyl, naphth-1-yl, naphth-2-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl,thien-2-yl, thien-3-yl, thiazol-2-yl and oxazol-2-yl groups, it beingpossible for this group Ar optionally to be substituted by one or moresubstituents chosen from halogen atoms and (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy,(C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio,(C₃-C₇)cycloalkyl(C₁-C₆)alkylthio, mono- or polyfluoro(C₁-C₆)alkyl andmono- or polyfluoro(C₁-C₆)alkyloxy groups,R represents either a hydrogen atom or one or more substituents,identical to or different from one another, chosen from halogen atomsand mono- or polyfluoro(C₁-C₆)alkyl and mono- orpolyfluoro(C₁-C₆)alkyloxy, linear (C₁-C₆)alkyl, branched or cyclic(C₃-C₇)alkyl, (C₃-C₇)cyclo alkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy,(C₁-C₆)alkylthio, cyano, amino, phenyl, acetyl, benzoyl,(C₁-C₆)alkylsulphonyl, carboxyl, (C₁-C₆)alkoxycarbonyl andpentafluorosulphanyl groups.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of general formula (I) have three asymmetric centers; theycan exist in the form of enantiomers or of threo or erythrodiastereoisomers with a cis or trans stereochemistry of the substituentof the bicycle, or as a mixture of such isomers. They can also exist inthe form of free bases, of addition salts with acids and/or of solvatesor of hydrates, namely in the form of combinations or associations withone or more molecules of water or with a solvent. Such hydrates andsolvates also form part of the invention.

Among the compounds of the invention, a first group of compounds iscomposed of the compounds for which:

Ar represents a group chosen from the phenyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, thien-2-yl and thien-3-yl groups, it beingpossible for this group Ar optionally to be substituted by one or moresubstituents chosen from halogen atoms and (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cyclo alkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy,(C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio,(C₃-C₇)cycloalkyl(C₁-C₆)alkylthio, mono- or polyfluoro(C₁-C₆)alkyl andmono- or polyfluoro(C₁-C₆)alkyloxy groups,m, n and R being as defined above.

Among the compounds of the invention, a second group of compounds iscomposed of the compounds for which:

Ar represents a group chosen from the phenyl, pyridin-3-yl andthien-3-yl groups, it being possible for this group Ar optionally to besubstituted by one or more substituents, identical to or different fromone another, chosen from halogen atoms,m, n and R being as defined above.

Among the compounds of the invention, a third group of compounds iscomposed of the compounds for which:

R represents either a hydrogen atom or one or more substituents,identical to or different from one another, chosen from halogen atomsand mono- or polyfluoro(C₁-C₆)alkyl, mono- or polyfluoro(C₁-C₆)alkyloxy,linear (C₁-C₆)alkyl and pentafluorosulphanyl groups,m, n and Ar being as defined above.

Among the compounds of the invention, a fourth group of compounds iscomposed of the compounds for which:

-   -   m and n each represent, independently of one another, the number        1 or 2,    -   Ar represents a group chosen from the phenyl, pyridin-3-yl and        thien-3-yl groups, it being possible for this group Ar        optionally to be substituted by one or more halogen atoms,    -   R represents either a hydrogen atom or one or more substituents,        identical to or different from one another, chosen from chlorine        and the methyl, trifluoromethyl, trifluoromethoxy and        pentafluorosulphanyl groups.

Among the compounds of the invention, a fifth group of compounds iscomposed of the following compounds:

-   trans-threo-2-Chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2-Chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2,6-Dichloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2,6-Dichloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   2-Chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   cis-erythro-2-Methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   2-Chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   2-Chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   cis-erythro-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   2-Chloro-N—[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   2-Chloro-N—[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2,6-Dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2,6-Dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2-Methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2,6-Dichloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2-Chloro-N-[(octahydroquinolizin-4-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-3-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]benzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-erythro-2-Chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide    hydrochloride 1:1.-   trans-threo-2-Chloro-3-methoxy-N-[(octahydroquinolizin-4-yl)phenylmethyl]benzamide    hydrochloride 1:1.-   trans-threo-N-[(Octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethoxybenzamide    hydrochloride 1:1.-   trans-threo-N-[(Octahydroquinolizin-4-yl)phenylmethyl]-3-(pentafluorosulphanyl)benzamide    hydrochloride 1:1.-   2-Chloro-N-[(hexahydropyrrolizin-3-yl)phenylmethyl]benzamide    hydrochloride 1:1.

The compounds of general formula (I) can be prepared by a processillustrated by the following Scheme 1.

A nitrile of general formula (II), in which m and n are as definedabove, is reacted with a lithiated derivative of general formula (III),in which Ar is as defined above, in an ethereal solvent, such as diethylether or tetrahydrofuran, between −90° C. and −30° C.; an intermediateimine of general formula (IV) is obtained and is reduced to a primaryamine of general formula (V) by a reducing agent, such as sodiumborohydride, in a protic solvent, such as methanol, between 0° C. andambient temperature. Amide coupling is subsequently carried out betweenthe diamine of general formula (V) and an activated acid or an acidchloride of general formula (VI), in which Y represents an activated OHgroup or a chlorine atom and R is as defined above, using the methodsknown to a person skilled in the art, to arrive at the amide of generalformula (I).

The compounds of general formula (II) with n=1 and m=2 have a cis andtrans relative stereochemistry and they result respectively in thecompounds of general formula (I) of cis-erythro and trans-threostereochemistry.

The compounds of general formula (II) with n=2 and m=1 or n and m=2 havea trans relative stereochemistry and they result in the compounds ofgeneral formula (I) of trans-erythro and trans-threo stereochemistry.

Finally, the compound of general formula (II) with n and m=1 has a transand cis relative stereochemistry and it results in the compounds ofgeneral formula (I) in the form of a mixture of isomers which can beseparated by liquid chromatography.

Furthermore, the chiral compounds of general formula (I) can be obtainedby separation of the racemic compounds by high performance liquidchromatography (HPLC) on a chiral column or by resolution of the racemicamine of general formula (V) by use of a chiral acid, such as tartaricacid, camphorsulphonic acid, dibenzoyltartaric acid or N-acetylleucine,by the fractional and preferential recrystallization of adiastereoisomeric salt in a solvent of alcohol type, or byenantioselective synthesis using a chiral nitrile of general formula(II).

The nitriles of general formula (II) are described in Synlett, (1995),519-522, when n and m represent 1 with a cis and trans stereochemistry,in J.O.C., 55, (1990), 4688-4693 and J.O.C., 56, (1991), 4868-4874, whenn represents 2 and m represents 1 with a trans stereochemistry, and inOrg. Letters, 2, (2000), 2085-2088, when n represents 1 and m represents2 with a trans and cis stereochemistry, and, finally, they can beprepared according to methods analogous to those described above when nand m represent 2 with a trans stereochemistry in the racemic or chiralseries. The lithiated derivatives of general formula (III) are availablecommercially or they can be prepared according to methods known to aperson skilled in the art and analogous to those described in J.O.C.,62, (1997), 5484-5496 and Tetrahedron Letters, 35, (1994), 3673-3674.

Certain acids and acid chlorides of general formula (VI) are availablecommercially or can be obtained according to methods analogous to thosedescribed in Patents EP-0 556 672 and U.S. Pat. No. 3,801,636 and in J.Chem. Soc., (1927), 25, Chem. Pharm. Bull., (1992), 1789-1792, Aust. J.Chem., (1984), 1938-1950 and J.O.C., (1980), 527.

The invention, according to another of its aspects, also has assubject-matter the compounds of general formula (V):

in whichm and n each represent, independently of one another, the number 1 or 2,Ar represents a group chosen from the phenyl, naphth-1-yl, naphth-2-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl,thien-2-yl, thien-3-yl, thiazol-2-yl and oxazol-2-yl groups, it beingpossible for this group Ar optionally to be substituted by one or moresubstituents chosen from halogen atoms and (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy,(C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio,(C₃-C₇)cycloalkyl(C₁-C₆)alkylthio, mono- or polyfluoro(C₁-C₆)alkyl andmono- or polyfluoro(C₁-C₆)alkyloxy groups.

These compounds are of use as intermediates in the synthesis of thecompounds of formula (I).

Among the compounds of general formula (V) which are a subject-matter ofthe invention, a first group of compounds is composed of the compoundsfor which:

m and n each represent, independently of one another, the number 1 or 2,Ar represents a group chosen from the phenyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, thien-2-yl and thien-3-yl groups, it beingpossible for this group Ar optionally to be substituted by one or moresubstituents chosen from halogen atoms and (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy,(C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio,(C₃-C₇)cycloalkyl(C₁-C₆)alkylthio, mono- or polyfluoro(C₁-C₆)alkyl andmono- or polyfluoro(C₁-C₆)alkyloxy groups.

Among the compounds of general formula (V) which are a subject-matter ofthe invention, a second group of compounds is composed of the compoundsfor which:

Ar represents a group chosen from the phenyl, pyridin-3-yl andthien-3-yl groups, it being possible for this group Ar optionally to besubstituted by one or more substituents chosen from halogen atoms,m and n being as defined above.

Among the compounds of general formula (V) which are a subject-matter ofthe invention, a third group of compounds is composed of the compoundsfor which:

-   -   m and n each represent, independently of one another, the number        1 or 2,    -   Ar represents a group chosen from the phenyl, pyridin-3-yl and        thien-3-yl groups, it being possible for this group Ar        optionally to be substituted by one or more halogen atoms.

Among the compounds of general formula (V), mention may in particular bemade of the following compounds:

-   trans-threo/erythro-1-(octahydroindolizin-5-yl)-1-phenylmethanamine;-   trans-threo-1-(octahydroindolizin-3-yl)-1-phenylmethanamine;-   cis-erythro-1-(octahydroindolizin-3-yl)-1-phenylmethanamine;-   trans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-phenylmethanamine;-   trans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-(4-fluorophenyl)methanamine;-   trans-threo-1-(octahydro-2H-quinolizin-4-yl)-1-(pyridin-3-yl)methanamine;-   trans-threo/cis-erythro-1-(octahydro-2H-quinolizin-4-yl)-1-(thien-3-yl)methanamine.

The examples which will follow illustrate the preparation of a fewcompounds of the invention. The elemental microanalyses, the IR and NMRspectra and chiral column HPLC confirm the structures and theenantiomeric purities of the compounds obtained.

The numbers shown in brackets in the titles of the examples correspondto those in the 1st column of the table given later.

Example 1 Compounds No. 1 and 2trans-threo-2-Chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andtrans-erythro-2-chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 1.1trans-threo/erythro-1-(octahydroindolizin-5-yl)-1-phenylmethanamine

0.62 g (4 mmol) of bromobenzene in solution in 5 ml of anhydroustetrahydrofuran is introduced, under an argon atmosphere, into a 50 mlround-bottomed flask equipped with a magnetic stirrer and then themedium is cooled to −75° C. 1.6 ml (4 mmol) of a 2.5M solution ofbutyllithium in tetrahydrofuran are added and the mixture is leftstirring for 40 min. 0.3 g (2 mmol) oftransoctahydroindolizine-5-carbonitrile in solution of 5 ml oftetrahydrofuran is added at −75° C. and the mixture is allowed to returnto ambient temperature over 3 h. Water and ethyl acetate are added andthe aqueous phase is separated and extracted with ethyl acetate. Thecombined organic phases are dried over sodium sulphate and filtered, andthe imine is concentrated under reduced pressure and taken up in a 50 mlround-bottomed flask with 10 ml of methanol. The mixture is cooled to−5° C. and 0.38 g (10 mmol) of sodium borohydride is slowly added.Stirring is continued while allowing the temperature of the mixture toreturn to ambient temperature over 12 h. The mixture is concentratedunder reduced pressure and the residue is taken up in water and ethylacetate. The phases are separated and the aqueous phase is extractedwith ethyl acetate. After washing the combined organic phases, dryingover sodium sulphate, filtering and evaporating, 0.5 g of product isobtained in the form of a yellow oil which is used as is in thefollowing stage.

1.2.trans-threo-2-Chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andtrans-erythro-2-chloro-N-[(octahydro-indolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1

0.5 g (2.17 mmol) of 1-(octahydroindolizin-5-yl)-1-phenylmethanamine,0.36 ml (2.6 mmol) of triethylamine and 0.63 g (2.6 mmol) of2-chloro-3-trifluoromethylbenzoic acid chloride are successivelyintroduced into 10 ml of dichloromethane in a 50 ml round-bottomed flaskand the mixture is stirred at ambient temperature for 1 h.

The mixture is treated with water and extracted several times withdichloromethane. After washing the organic phases with water and thenwith a 1N aqueous sodium hydroxide solution, drying over magnesiumsulphate, filtering and evaporating the solvent under reduced pressure,the residue is purified by chromatography on a column of silica gel,elution being carried out with a mixture of dichloromethane andmethanol.

0.06 g and 0.130 g of products corresponding to the trans-threo andtrans-erythro isomers are obtained in the form of a colorless oil.

These products are subsequently converted to hydrochlorides startingfrom a 0.1N solution of hydrochloric acid in propan-2-ol.

Finally, 0.039 g corresponding to the trans-threo isomer is isolated,

Melting point: 132-134° C.,

¹H NMR (200 MHz, CDCl₃): 0.75-2.00 (m, 12H), 2.6-2.9 (m, 2H), 5.00 (d,1H), 7.1-7.5 (m, 7H), 7.8 (t, 2H);

and 0.017 g corresponding to the trans-erythro isomer is isolated,

Melting point: 132-134° C.,

¹H NMR (200 MHz, CDCl₃): 0.70-2.00 (m, 11H), 2.1-2.45 (m, 2H), 3.15-3.35(m, 1H), 5.20 (s, 1H), 6.9 (s, 1H), 7.1-7.4 (m, 6H), 7.6-7.75 (m, 2H).

Example 2 Compound No. 5trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1.1 2.1.trans-threo-1-(Octahydroindolizin-3-yl)-1-phenylmethanamine

0.61 g (4.12 mmol) of trans-octahydroindolizine-3-carbonitrile, insolution in 25 ml of anhydrous tetrahydrofuran, is introduced, under anargon atmosphere, into a 100 ml round-bottomed flask equipped with amagnetic stirrer. The medium is cooled to −75° C., 6.22 ml (12.24 mmol)of a 2M solution of phenyllithium in dibutyl ether are added and themixture is allowed to return, with stirring to ambient temperature over5 h. 3 ml of methanol are added, then water and ethyl acetate are addedand the aqueous phase is separated and extracted with ethyl acetate. Thecombined organic phases are dried over sodium sulphate and filtered, andthe imine is concentrated under reduced pressure and taken up in a 50 mlround-bottomed flask with 25 ml of methanol. The mixture is cooled to−5° C. and 0.78 g (20.6 mmol) of sodium borohydride is slowly added.Stirring is continued while allowing the mixture to return to ambienttemperature over 12 h. The mixture is concentrated under reducedpressure, the residue is taken up in water and ethyl acetate, the phasesare separated and the aqueous phase is extracted with ethyl acetate.After washing the combined organic phases, drying over sodium sulphate,filtering and evaporating, 0.8 g of product is obtained in the form of ayellow oil which is used as is in the following stage.

2.2.trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1

0.4 g (1.77 mmol) oftrans-threo-1-(octahydroindolizin-3-yl)-1-phenylmethanamine, 0.3 ml (2.1mmol) of triethylamine and 0.57 g (2.35 mmol) of2-chloro-3-trifluoromethylbenzoic acid chloride are successivelyintroduced into 15 ml of dichloromethane in a 50 ml round-bottomed flaskand the mixture is stirred at ambient temperature for 12 h.

It is treated with water and extracted several times withdichloromethane. After washing the organic phases with water and thenwith a 1N aqueous sodium hydroxide solution, drying over magnesiumsulphate, filtering and evaporating the solvent under reduced pressure,the residue is purified by chromatography on a column of silica gel,elution being carried out with a mixture of dichloromethane andmethanol.

0.35 g of product corresponding to the trans-threo isomer is obtained inthe form of a colorless oil.

It is converted to the hydrochloride from a 0.1N solution ofhydrochloric acid in propan-2-ol.

Finally, 0.28 g is isolated in the form of a white solid.

Melting point: 138-139° C.,

¹H NMR (200 MHz, CDCl₃): 1.0-1.9 (m, 10H), 2.9 (t, 1H), 3.05-3.25 (m,2H), 3.5-3.6 (m, 1H), 5.20 (d, 1H), 7.3-7.5 (m, 6H), 7.8 (t, 2H).

Example 3 Compound No. 11cis-erythro-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 3.1.cis-erythro-1-(octahydroindolizin-3-yl)-1-phenylmethanamine

According to the protocol described in Example 1.1, starting from 0.61 g(4 mmol) of cis-octahydroindolizine-3-carbonitrile, 0.9 g of product isobtained in the form of a yellow oil which is used as is in thefollowing stage.

¹H NMR (200 MHz, CDCl₃): 1.00-2.00 (m, 12H), 2.35-2.50 (m, 1H),3.00-3.15 (m, 1H), 4.15 (d, 1H), 7.1-7.4 (m, 5H).

3.2.cis-erythro-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1

According to the protocol described in Example 2.2, starting from 0.47 g(2 mmol) of cis-erythro-1-(octahydroindolizin-3-yl)-1-phenylmethanamineand 0.58 g (2.4 mmol) of 2-chloro-3-trifluoromethylbenzoic acidchloride, 0.44 g is obtained in the form of a colorless oilcorresponding to the cis-erythro isomer.

This product is subsequently converted to the hydrochloride from a 0.1Nsolution of hydrochloric acid in propan-2-ol.

Finally, 0.28 g is isolated in the form of a white solid.

Melting point: 138-139° C.,

¹H NMR (200 MHz, CDCl₃): 0.09-1.0 (m, 1H), 1.1-1.35 (m, 5H), 1.4-1.55(m, 2H), 1.65-1.9 (m, 3H), 2.00-2.15 (m, 1H), 2.7-2.80 (m, 1H),3.20-3.30 (m, 1H), 5.25 (t, 1H), 7.3-7.6 (m, 6H), 7.8-7.9 (m, 2H).

Example 4 Compounds No. 14 and 21trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andtrans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 4.1.trans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-phenylmethanamine

0.29 g (1.77 mmol) of trans-octahydroquinolizine-4-carbonitrile, insolution in 10 ml of anhydrous tetrahydrofuran, is introduced, under anargon atmosphere, into a 50 ml round-bottomed flask equipped with amagnetic stirrer. The medium is cooled to −75° C., 2 ml (4 mmol) of a 2Msolution of phenyllithium in cyclohexane/ethyl ether (70/30) are addedand the mixture is allowed to return to −50° C. with stirring over 3 h.1 ml of methanol is added, then water and ethyl acetate are added at 25°C. and the aqueous phase is separated and extracted with ethyl acetate.The combined organic phases are dried over sodium sulphate and filtered,and the imine is concentrated under reduced pressure and taken up in a50 ml round-bottomed flask with 10 ml of methanol. The mixture is cooledto −5° C. and 0.33 g (8.85 mmol) of sodium borohydride is slowly added.Stirring is continued while allowing the mixture to return to ambienttemperature over 12 h. The mixture is concentrated under reducedpressure and the residue is taken up in water and ethyl acetate. Thephases are separated and the aqueous phase is extracted with ethylacetate. After washing the combined organic phases, drying over sodiumsulphate, filtering and evaporating, 0.18 g of product is obtained inthe form of a yellow oil which is used as is in the following stage.

4.2.trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andtrans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride 1:1

0.18 g (0.74 mmol) oftrans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-phenylmethanamine,0.20 g (0.89 mmol) of 2-chloro-3-trifluoromethylbenzoic acid, 0.17 g(0.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI) and 0.045 g (0.37 mmol) of dimethylaminopyridineare successively introduced into 10 ml of dichloromethane in a 50 mlround-bottomed flask and the mixture is stirred at ambient temperaturefor 12 h.

It is treated with water and extracted several times withdichloromethane. After washing the organic phases with water and thenwith a 1N aqueous sodium hydroxide solution, drying over magnesiumsulphate, filtering and evaporating the solvent under reduced pressure,the residue is purified by chromatography on a column of silica gel,elution being carried out with a mixture of dichloromethane andmethanol.

0.13 g of compound corresponding to the trans-threo isomer and 0.024 gof compound corresponding to the trans-erythro isomer are obtained inthe colorless oil form.

They are converted to hydrochlorides from a 0.1N solution ofhydrochloric acid in propan-2-ol.

Finally, 0.13 g is isolated in the form of a white solid formed oftrans-threo isomer:

Melting point: 161-163° C.,

¹H NMR (200 MHz, C₅D₅N): 1.2-2.0 (m, 10H), 2.15-2.35 (m, 2H), 3.2 (t,1H), 3.65-3.8 (m, 1H), 3.85-4.0 (m, 2H), 6.30 (d, 1H), 7.3-7.6 (m, 6H),7.8 (d, 2H); and 0.014 g is isolated in the form of a white solid formedof trans-erythro isomer:

Melting point: 245-247° C.,

¹H NMR (200 MHz, C₅D₅N): 1.0-2.1 (m, 12H), 2.3-2.6 (m, 2H), 3.00 (d,1H), 4.0 (d, 1H), 6.30 (d, 1H), 7.2-7.8 (m, 7H), 8.3 (d, 1H).

Example 5 Compounds No. 26 and 27trans-threo-2-Chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andtrans-erythro-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1 5.1.trans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-(4-fluorophenyl)methanamine

1.33 g (7.61 mmol) of 1-bromo-4-fluorobenzene, in solution in 10 ml ofanhydrous ethyl ether, are introduced, under an argon atmosphere, into a50 ml round-bottomed flask equipped with a magnetic stirrer and then themedium is cooled to −75° C. 3.35 ml (8.37 mmol) of a 2.5M solution ofbutyllithium in hexane are subsequently added and the mixture is allowedto return to −40° C. with stirring over 90 min. 0.5 g (3 mmol) oftrans-octahydroquinolizine-4-carbonitrile, in solution in 10 ml of ethylether, is subsequently added at −75° C. and this temperature ismaintained for 90 min. The mixture is allowed to return to 0° C. and 2ml of methanol are added, then, at 25° C., water and ethyl acetate areadded and the aqueous phase is separated and extracted with ethylacetate. The combined organic phases are dried over sodium sulphate andfiltered, and the imine is concentrated under reduced pressure in orderto be taken up in a 50 ml round-bottomed flask with 20 ml of methanol.The mixture is cooled to −5° C. and 0.57 g (15.2 mmol) of sodiumborohydride is slowly added. Stirring is continued while allowing themixture to return to ambient temperature over 12 h. The mixture isconcentrated under reduced pressure and the residue is taken up in waterand ethyl acetate. The phases are separated and the aqueous phase isextracted with ethyl acetate. After washing the combined organic phases,drying with sodium sulphate, filtering and evaporating, 0.97 g ofproduct is obtained in the form of a yellow oil which is used as is inthe following stage.

5.2.trans-threo-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andtrans-erythro-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1

0.4 g (1.52 mmol) oftrans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-(4-fluorophenyl)methanamine,0.23 ml (1.8 mmol) of triethylamine and 0.4 g (1.67 mmol) of2-chloro-3-trifluoromethylbenzoic acid chloride are successivelyintroduced into 10 ml of dichloromethane in a 50 ml round-bottomed flaskand the mixture is stirred at ambient temperature for 12 h.

The mixture is treated with water and extracted several times withdichloromethane. After washing the organic phases with water and thenwith a 1N aqueous sodium hydroxide solution, drying over magnesiumsulphate, filtering and evaporating the solvent under reduced pressure,the residue is purified by chromatography on a column of silica gel,elution being carried out with a mixture of dichloromethane andmethanol.

0.11 g of compound corresponding to the trans-threo isomer and 0.15 g ofcompound corresponding to the trans-erythro isomer are obtained in thecolorless oil form.

These products are subsequently converted to hydrochlorides from a 0.1Nsolution of hydrochloric acid in propan-2-ol.

Finally, 0.082 g of trans-threo isomer is isolated in the form of awhite solid:

Melting point: 176-178° C.,

¹H NMR (200 MHz, CDCl₃): 1.3-2.3 (m, 12H), 2.6-2.85 (m, 1H), 3.2 (t,1H), 3.55-3.8 (m, 2H), 5.65 (t, 1H), 7.15 (t, 2H), 7.35 (t, 2H), 7.5 (t,1H), 7.8 (d, 1H), 8.05 (d, 1H), 8.75 (d, 1H, NH); and 0.095 g oftrans-erythro isomer is isolated in the form of a white solid:

Melting point: 188-189° C.,

¹H NMR (200 MHz, CDCl₃): 1.1-2.6 (m, 12H), 2.7-3.2 (m, 3H), 3.95 (d,1H), 5.80 (t, 1H), 7.15 (t, 2H), 7.35 (t, 2H), 7.5 (t, 1H), 7.8 (d, 1H),7.95 (d, 1H), 9.3 (d, 1H, NH).

Example 6 Compound No. 20trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1. 6.1.trans-threo-1-(octahydro-2H-quinolizin-4-yl)-1-(pyridin-3-yl)methanamine

According to the protocol described in Example 5.1, starting from 0.8 g(5.32 mmol) of 3-bromopyridine and 0.35 g (2.13 mmol) oftrans-octahydroquinolizine-4-carbonitrile, 0.57 g of product is obtainedin the form of a brown oil which is used as is in the following stage.

6.2.trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1

According to the protocol described in Example 5.2, starting from 0.57 g(2.32 mmol) oftrans-threo-1-(octahydro-2H-quinolizin-4-yl)-1-(pyridin-3-yl)methanamineand 0.62 g (2.55 mmol) of 2-chloro-3-trifluoromethylbenzoic acidchloride, 0.21 g of compound corresponding to the trans-threo isomer isobtained.

This product is subsequently converted to the hydrochloride from a 0.1Nsolution of hydrochloric acid in propan-2-ol.

Finally, 0.042 g of trans-threo isomer is isolated in the form of awhite solid:

Melting point: 236-238° C.

¹H NMR (200 MHz, CDCl₃): 1.3-2.4 (m, 12H), 2.6-2.9 (m, 1H), 3.2 (t, 1H),3.65-3.90 (m, 2H), 5.75 (t, 1H), 7.3-7.55 (m, 2H), 7.8 (t, 2H), 8.05 (d,1H), 8.65 (d, 1H), 8.8 (s, 1H), 9.1 (d, 1H, NH).

Example 7 Compounds No. 10 and 12trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)(thien-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andcis-erythro-2-chloro-N-[(octahydroindolizin-3-yl)(thien-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1 7.1.trans-threo/cis-erythro-1-(octahydro-2H-quinolizin-4-yl)-1-(thien-3-yl)methanamine

According to the protocol described in Example 5.1, starting from 1.1 g(6.9 mmol) of 3-bromothiophene and 0.41 g (2.76 mmol) of a trans/cischiral mixture of octahydroindolizine-5-carbonitrile, 0.51 g of productis obtained in the form of a brown oil which is used as is in thefollowing stage.

7.2.trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)(thien-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1 andcis-erythro-2-chloro-N-[(octahydroindolizin-3-yl)(thien-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride 1:1

According to the protocol described in Example 5.2, starting from 0.51 g(2.15 mmol) oftrans-threo/cis-erythro-1-(octahydro-2H-quinolizin-4-yl)-1-(thien-3-yl)methanamineand 0.57 g (2.37 mmol) of 2-chloro-3-trifluoromethylbenzoic acidchloride, 0.25 g of compound corresponding to the trans-threo isomer and0.14 g of compound corresponding to the cis-erythro isomer are obtained.

These products are subsequently converted to hydrochlorides from a 0.1Nsolution of hydrochloric acid in propan-2-ol.

Finally, 0.22 g of trans-threo isomer is isolated in the form of a whitesolid (RSS stereochemistry):

Melting point: 159-161° C.,

[α]_(D)=−55.2° (c=1.01, MeOH),

¹H NMR (200 MHz, CDCl₃): 1.1-2.2 (m, 10H), 2.85 (t, 1H), 3.0-3.2 (m,2H), 3.55-3.70 (m, 1H), 5.4 (t, 1H), 7.1 (d, 1H), 7.2-7.35 (m, 2H), 7.5(t, 1H), 7.8 (t, 2H);

and 0.16 g of cis-erythro isomer is isolated in the form of a whitesolid (RSS stereochemistry):

Melting point: 170-172° C.,

[α]_(D)=+46.8° (c=1.02, MeOH),

¹H NMR (200 MHz, CDCl₃): 1.1-1.9 (m, 10H), 2.0-2.2 (m, 2H), 2.75-2.9 (m,1H), 3.25 (d, 1H), 5.4 (t, 1H), 7.1 (d, 1H), 7.2 (s, 1H), 7.35 (d, 1H),7.5 (t, 1H), 7.8 (t, 2H).

The stereochemistry of the compounds is illustrated on the followingpage.

The chemical structures and the physical properties of a few compoundsof the invention are illustrated in the following table.

In the “Ar” column, C₆H₅ denotes a phenyl group, z-X—C₆H₄ denotes aphenyl group substituted by X in the z position, C₅H₄N-3 denotes apyridin-3-yl group and C₄H₃S-3 denotes a thien-3-yl group.

In the “Salt” column “-” denotes a compound in the base state and “HCl”denotes a hydrochloride.

In the “M.p. (° C.)” column, (d) denotes a melting point withdecomposition.

In the “St.” column, t-t denotes a trans-threo configuration, t-edenotes a trans-erythro configuration, c-e denotes a cis-erythroconfiguration and rac. denotes a racemate.

TABLE (I)

No. m n Ar R Salt M.p. (° C.) St. 1 1 2 C₆H₅ 2-Cl, 3-CF₃ HCl 132-134 t-t(rac.) 2 1 2 C₆H₅ 2-Cl, 3-CF₃ HCl 132-134 t-e (rac.) 3 1 2 C₆H₅2,6-(Cl)₂, 3-CF₃ HCl 206-208 t-t (rac.) 4 1 2 C₆H₅ 2,6-(Cl)₂, 3-CF₃ HCl254-256 t-e (rac.) 5 2 1 C₆H₅ 2-Cl, 3-CF₃ HCl 138-139 t-t (rac.) 6 2 1C₆H₅ 2-Cl, 3-CF₃ HCl 240 (d) t-t (RSS) 7 2 1 C₆H₅ 2-CH₃, 3-CF₃ HCl140-141 t-t (rac.) 8 2 1 C₆H₅ 2-CH₃, 3-CF₃ HCl 247-248 c-e (rac.) 9 2 1C₅H₄N-3 2-Cl, 3-CF₃ HCl 145-147 t-t (RSS) 10 2 1 C₄H₃S-3 2-Cl, 3-CF₃ HCl159-161 t-t (RSS) 11 2 1 C₆H₅ 2-Cl, 3-CF₃ HCl 138-139 c-e (Rac.) 12 2 1C₄H₃S-3 2-Cl, 3-CF₃ HCl 170-172 c-e (RRS) 13 2 1 C₅H₄N-3 2-Cl, 3-CF₃ HCl131-133 c-e (RRS) 14 2 2 C₆H₅ 2-Cl, 3-CF₃ HCl 161-163 t-t (rac.) 15 2 2C₆H₅ 2-Cl, 5-CF₃ HCl 142-144 t-e (rac.) 16 2 2 C₆H₅ 2,6-(Cl)₂, 3-CF₃ HCl286-288 t-t (rac.) 17 2 2 C₆H₅ 2,6-(Cl)₂, 3-CF₃ HCl 205 (d) t-e (rac.)18 2 2 C₆H₅ 2-CH₃, 3-CF₃ HCl 166-167 t-e (rac.) 19 2 2 4-F—C₆H₄2,6-(Cl)₂, 3-CF₃ HCl 289-291 t-t (rac.) 20 2 2 C₅H₄N-3 2-Cl, 3-CF₃ HCl236-238 t-t (rac.) 21 2 2 C₆H₅ 2-Cl, 3-CF₃ HCl 245-247 t-e (rac.) 22 2 2C₆H₅ 2-Cl, 5-CF₃ HCl 255-257 t-t (rac.) 23 2 2 C₆H₅ 2-CH₃, 3-CF₃ HCl141-143 t-t (rac.) 24 2 2 C₄H₃S-3 2-Cl, 3-CF₃ HCl 157-159 t-e (rac.) 252 2 C₆H₅ 2-Cl, 3-CH₃ HCl 171-173 t-t (rac.) 26 2 2 4-F—C₆H₄ 2-Cl, 3-CF₃HCl 176-178 t-t (rac.) 27 2 2 4-F—C₆H₄ 2-Cl, 3-CF₃ HCl 188-189 t-e(rac.) 28 2 2 C₆H₅ 2-CH₃, 3-OCH₃ HCl 224-226 t-t (rac.) 29 2 2 C₆H₅3-OCF₃ HCl 258-260 t-t (rac.) 30 2 2 C₆H₅ 3-SF₆ HCl 248-250 t-t (rac.)31 1 1 C₆H₅ 2-Cl, 3-CF₃ — MH⁺ = 423 —

The compounds of the invention have been subjected to a series ofpharmacological trials which have demonstrated their advantage assubstances possessing therapeutic activities.

Study of glycine transportation in SK-N-MC cells expressing the nativehuman transporter GlyT1.

The uptake of [¹⁴C]glycine is studied in SK-N-MC cells (humanneuroepithelial cells) expressing the native human transporter GlyT1 bymeasuring the radioactivity incorporated in the presence or absence ofthe test compound. The cells are cultured as a monolayer for 48 hours inplates pretreated with 0.02% fibronectin. On the day of the experiment,the culture medium is removed and the cells are washed with Krebs-HEPES(4-(2-hydroxyethyl)piperazine-1-ethanesulphonic acid) buffer at pH 7.4.After preincubation for 10 minutes at 37° C. in the presence either ofbuffer (control batch) or of test compound at various concentrations orof 10 mM of glycine (determination of the non-specific uptake), 10 μM of[¹⁴C]glycine (specific activity 112 mCi/mmol) are subsequently added.Incubation is continued for 10 min at 37° C. and the reaction is haltedby washing twice with pH 7.4 Krebs-HEPES buffer. The radioactivityincorporated by the cells is then estimated after adding 100 μl ofliquid scintillant and stirring for 1 h. Counting is carried out on aMicrobeta Tri-Lux™ counter. The effectiveness of the compound isdetermined by the IC₅₀, the concentration of the compound which reducesby 50% the specific uptake of glycine, defined by the difference inradioactivity incorporated by the control batch and the batch whichreceived the 10 mM glycine.

The compounds of the invention have, in this test, an IC₅₀ of the orderof 0.001 to 0.20 μM.

Compound 1 IC₅₀ = 0.08 μM Compound 2 IC₅₀ = 0.023 μM Compound 5 IC₅₀ =0.003 μM

As shown by these results, the compounds of the invention exhibit aspecific activity as inhibitors of the glycine transporters GlyT1.

The compounds according to the invention can thus be used in thepreparation of medicaments, in particular of medicaments which areinhibitors of GlyT1 glycine transporters.

These results suggest that the compounds of the invention can be usedfor the treatment of behavioral disorders associated with dementia,psychoses, in particular schizophrenia (deficit form and productiveform) and acute or chronic extrapyramidal symptoms induced byneuroleptics, for the treatment of various forms of anxiety, panicattacks, phobias, obsessive-compulsive disorders, for the treatment ofvarious forms of depression, including psychotic depression, for thetreatment of disorders due to alcohol abuse or withdrawal, disorders ofsexual behavior, eating disorders, for the treatment of migraine or inthe treatment of primary generalized epilepsy, secondary generalizedepilepsy, partial epilepsy with a simple or complex symptomatology,mixed forms and other epileptic syndromes, in complementing anotherantiepileptic treatment or in monotherapy.

This is why another subject-matter of the present invention ispharmaceutical compositions comprising an effective dose of at least onecompound according to the invention, in the form of the base or apharmaceutically acceptable salt or solvate, as a mixture, ifappropriate, with suitable excipients.

The said excipients are chosen according to the pharmaceutical form andthe method of administration desired.

The pharmaceutical compositions according to the invention may thus beintended for oral, sublingual, subcutaneous, intramuscular, intravenous,topical, intratracheal, intranasal, transdermal, rectal or intraocularadministration.

The unit administration forms can be, for example, tablets, gelatincapsules, granules, powders, solutions or suspensions to be taken orallyor to be injected, transdermal patches or suppositories. Ointments,lotions and collyria can be envisaged for topical administration.

The said unit forms are dosed to allow a daily administration of 0.01 to20 mg of active principle per kg of body weight, according to thepharmaceutical dosage form.

To prepare tablets, a pharmaceutical vehicle, which can be composed ofdiluents, such as, for example, lactose, microcrystalline cellulose orstarch, and formulation adjuvants, such as binders(polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like), flowagents, such as silica, or lubricants, such as magnesium stearate,stearic acid, glyceryl tribehenate or sodium stearylfumarate, is addedto the micronized or unmicronized active principle. Wetting orsurface-active agents, such as sodium lauryl sulphate, can also beadded.

The preparation techniques can be direct tableting, dry granulation, wetgranulation or hot melt.

The tablets can be bare, coated with sugar, for example with sucrose, orcoated with various polymers or other appropriate materials. They can bedesigned to make possible rapid, delayed or sustained release of theactive principle by virtue of polymer matrices or of specific polymersused in the coating.

To prepare gelatin capsules, the active principle is mixed with drypharmaceutical vehicles (simple mixing, dry or wet granulation, or hotmelt) or liquid or semisolid pharmaceutical vehicles.

The gelatin capsules can be hard or soft and coated or uncoated with athin film, so as to have a rapid, sustained or delayed activity (forexample, for an enteric form).

A composition in the form of a syrup or an elixir or for administrationin the form of drops can comprise the active principle in conjunctionwith a sweetener, preferably a calorie-free sweetener, methylparaben orpropylparaben, as antiseptic, a flavor enhancer and a colorant.

The water-dispersible powders and granules can comprise the activeprinciple as a mixture with dispersing agents or wetting agents, ordispersing agents, such as polyvinylpyrrolidone, as well as withsweeteners and flavor-correcting agents.

Recourse is had, for rectal administration, to suppositories preparedwith binders which melt at the rectal temperature, for example cocoabutter or polyethylene glycols.

Use is made, for parental administration, of aqueous suspensions,isotonic saline solutions or injectable sterile solutions comprisingpharmacologically compatible dispersing agents and/or wetting agents,for example propylene glycol or butylene glycol.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives or elsewith a polymer matrix or with a cyclodextrin (transdermal patches orsustained release forms).

The topical compositions according to the invention comprise a mediumcompatible with the skin. They can be provided in particular in the formof aqueous, alcoholic or aqueous/alcoholic solutions, of gels, ofwater-in-oil or oil-in-water emulsions having the appearance of a creamor of a gel, of microemulsions or of aerosols or in the form ofvesicular dispersions comprising ionic and/or nonionic lipids. Thesepharmaceutical dosage forms are prepared according to methodsconventional in the fields under consideration.

Finally, the pharmaceutical compositions according to the invention cancomprise, in addition to a compound of the general formula (I), otheractive principles which can be of use in the treatment of the disordersand diseases indicated above.

1. A method for treating a disease selected from the group consisting ofbehavioral disorders associated with dementia, psychoses, schizophrenia,acute or chronic extrapyramidal symptoms induced by neuroleptics,anxiety, panic attacks, phobias, obsessive-compulsive disorders,depression, psychotic depression, disorders due to alcohol abuse orwithdrawal, disorders of sexual behavior, eating disorders, migraine,and epilepsy, in a patient comprising administering to said patient atherapeutically effective amount of a compound corresponding to formula(I):

wherein: m and n each represent, independently of one another, 1 or 2;Ar represents a group chosen from phenyl, naphth-1-yl, naphth-2-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl,thien-2-yl, thien-3-yl, thiazol-2-yl and oxazol-2-yl groups, and whereinthe Ar group is optionally substituted by one or more substituentsselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy,(C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio,(C₃-C₇)cycloalkyl-(C₁-C₆)alkylthio, mono- or polyfluoro(C₁-C₆)alkyl andmono- or polyfluoro(C₁-C₆)alkyloxy groups; and R represents either ahydrogen atom or one or more substituents, identical to or differentfrom one another, chosen from halogen atoms and mono- orpolyfluoro(C₁-C₆)alkyl and mono- or polyfluoro(C₁-C₆)alkyloxy, linear(C₁-C₆)alkyl, branched or cyclic (C₃-C₇)alkyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyloxy,(C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy, (C₁-C₆)alkylthio, cyano, amino,phenyl, acetyl, benzoyl, (C₁-C₆)alkylsulphonyl, carboxyl,(C₁-C₆)alkoxycarbonyl and pentafluorosulphanyl groups; or an additionsalt thereof with an acid; or a solvate or hydrate of said compound orsaid salt; wherein said compound is in the form of a pure enantiomer orof an erythro or threo diastereoisomer or of a mixture of such isomers.2. The method according to claim 1, wherein, for the compound of formula(I): Ar represents a group chosen from phenyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, thien-2-yl and thien-3-yl groups, andwherein the Ar group is optionally substituted by one or moresubstituents, which are identical to or different from one another,chosen from halogen atoms and (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cyclo alkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyloxy,(C₃-C₇)cycloalkyl(C₁-C₆)alkyloxy, (C₁-C₆)alkylthio,(C₃-C₇)cycloalkylthio, (C₃-C₇)cycloalkyl(C₁-C₆)alkylthio, mono- orpolyfluoro(C₁-C₆)alkyl and mono- or polyfluoro(C₁-C₆)alkyloxy groups; oran addition salt thereof with an acid; or a solvate or hydrate of saidcompound or said salt.
 3. The method according to claim 1, wherein, forthe compound of formula (I): Ar represents a group chosen from thephenyl, pyridin-3-yl and thien-3-yl groups, and wherein the Ar group isoptionally substituted by one or more substituents, identical to ordifferent from one another, chosen from halogen atoms; or an additionsalt thereof with an acid; or a solvate or hydrate of said compound orsaid salt.
 4. The method according to claim 1, wherein, for the compoundof formula (I): R represents either a hydrogen atom or one or moresubstituents, which are identical to or different from one another,chosen from halogen atoms and mono- or polyfluoro(C₁-C₆)alkyl, mono- orpolyfluoro(C₁-C₆)alkyloxy, linear (C₁-C₆)alkyl and pentafluorosulphanylgroups; or an addition salt thereof with an acid; or a solvate orhydrate of said compound or said salt.
 5. The method according to claim1, wherein, for the compound of formula (I): R represents either ahydrogen atom or one or more substituents, which are identical to ordifferent from one another, chosen from halogen atoms and mono- orpolyfluoro(C₁-C₆)alkyl, mono- or polyfluoro(C₁-C₆)alkyloxy, linear(C₁-C₆)alkyl and pentafluorosulphanyl groups; or an addition saltthereof with an acid; or a solvate or hydrate of said compound or saidsalt.
 6. The method according to claim 1, wherein, for the compound offormula (I): R represents either a hydrogen atom or one or moresubstituents, which are identical to or different from one another,chosen from halogen atoms and mono- or polyfluoro(C₁-C₆)alkyl, mono- orpolyfluoro(C₁-C₆)alkyloxy, linear (C₁-C₆)alkyl and pentafluorosulphanylgroups; or an addition salt thereof with an acid; or a solvate orhydrate of said compound or said salt.
 7. The method according to claim1, wherein, for the compound of formula (I): m and n each represent,independently of one another, 1 or 2; Ar represents a group chosen fromthe phenyl, pyridin-3-yl and thien-3-yl groups, and wherein the Ar groupis optionally substituted by one or more halogen atoms; R representseither a hydrogen atom or one or more substituents, identical to ordifferent from one another, chosen from chlorine and methyl,trifluoromethyl, trifluoromethoxy and pentafluorosulphanyl groups; or anaddition salt thereof with an acid; or a solvate or hydrate of saidcompound or said salt.
 8. The method according to claim 1, wherein thecompound is selected from the group consisting of:trans-threo-2-chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2-chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2,6-dichloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2,6-dichloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;2-chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;cis-erythro-2-methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;2-chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;2-chloro-N—[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;cis-erythro-2-chloro-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;2-chloro-N—[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;2-chloro-N—[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethylbenzamidehydrochloride;trans-threo-2,6-dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2,6-dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2,6-dichloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethylbenzamidehydrochloride;trans-threo-2-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2-chloro-N-[(octahydroquinolizin-4-yl)(thiophen-3-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-chloro-3-methyl-N-[(octahydroquinolizin-4-yl)phenylmethyl]benzamidehydrochloride;trans-threo-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;trans-erythro-2-chloro-N-[(4-fluorophenyl)(octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamidehydrochloride;trans-threo-2-chloro-3-methoxy-N-[(octahydroquinolizin-4-yl)phenylmethyl]benzamidehydrochloride;trans-threo-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethoxybenzamidehydrochloride;trans-threo-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-(pentafluorosulphanyl)benzamidehydrochloride; and2-chloro-N-[(hexahydropyrrolizin-3-yl)phenylmethyl]benzamidehydrochloride.
 9. The method according to claim 1, wherein the compoundinhibits the GlyT1 glycine transporters.
 10. The method according toclaim 2, wherein the compound inhibits the GlyT1 glycine transporters.11. The method according to claim 3, wherein the compound inhibits theGlyT1 glycine transporters.
 12. The method according to claim 4, whereinthe compound inhibits the GlyT1 glycine transporters.
 13. The methodaccording to claim 5, wherein the compound inhibits the GlyT1 glycinetransporters.
 14. The method according to claim 6, wherein the compoundinhibits the GlyT1 glycine transporters.
 15. The method according toclaim 7, wherein the compound inhibits the GlyT1 glycine transporters.16. The method according to claim 8, wherein the compound inhibits theGlyT1 glycine transporters.